Compositions and methods for opioid antagonist delivery

ABSTRACT

Disclosed in certain embodiments is a pharmaceutical formulation (e.g., parenteral formulation) comprising a therapeutically effective amount of nalmefene or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable adjuvant (e.g., parenterally acceptable adjuvant) that promotes the rate at which the nalmefene or salt thereof is more rapidly absorbed into the systemic circulation of a subject identified as in need thereof.

FIELD OF THE INVENTION

In certain embodiments, the present invention relates to the field ofpharmaceutical compositions for rescuing a subject from an opioidoverdose, methods of providing overdose rescue, pre-dosing a subject asprotection against opioid overdose prior to entering an environmentwhere opioid exposure may occur, methods for treating alcoholdependence, methods for treating constipation, and drug delivery systemsthereof.

BACKGROUND OF THE INVENTION

Pharmaceutical products are sometimes subject to abuse. For example, aparticular dose of opioid analgesic may be more potent when administeredparenterally as compared to the same dose administered orally. Abusing apharmaceutical product may result in an overdose that could be fatal.Also, potent opioids can be used as toxic chemical agents intentionallyor unintentionally to cause death in humans through exposing humans tolethal doses through aerosolizing or other means of dispersal.

Symptoms of opioid overdose include, but not limited to, loss ofconsciousness, unresponsiveness to outside stimulus, being awake butunable to talk, respiratory depression or respiratory cessation,vomiting, limp body, pale or clammy skin, bluish fingernails and lips,slow heartbeat, erratic heartbeat, no heartbeat and eventual death.

To counteract opioid overdose effects, emergency personnel or others mayadminister an antidote such as an intramuscular injection of an opioidantagonist. Given that the administered antidote needs to be absorbedinto the bloodstream, there inevitably will be a lag from the time ofantidote administration to the time that the antidote reachestherapeutic levels sufficient to effectively counteract the effects ofthe opioid. Unfortunately, this lag time can result in the antidotetreatment not being effective enough in sufficient time to preventmorbidity and mortality due to the overdose.

There exists a need in the art for a pharmaceutical composition forrescuing a subject from opioid overdose, and a method of rescuing asubject from an opioid overdose which method provides a rapid onset ofaction.

OBJECTS AND SUMMARY OF THE INVENTION

It is an object of certain embodiments of the present invention toprovide a pharmaceutical composition (e.g., a parenteral formulation)for rescuing a subject from an opioid overdose, or for preventing (orreducing the risk in) a subject from experiencing an opioid overdose.

It is an object of certain embodiments of the present invention toprovide a parenteral formulation for rescuing a subject from an opioidoverdose, or for preventing (or reducing the risk in) a subject fromexperiencing an opioid overdose.

It is an object of certain embodiments of the present invention toprovide a method for rescuing a subject from an opioid overdose, or forpreventing (or reducing the risk in) a subject from experiencing anopioid overdose.

It is an object of certain embodiments of the present invention toprovide a method of prophylactically administering a pharmaceuticalcomposition as disclosed herein to a subject (e.g., a first responder ora member of law enforcement) who is at risk of being exposed to a toxicamount of an opioid agonist (e.g., fentanyl, sufentanyl, carfentanyl, ora salt or derivative thereof).

It is an object of certain embodiments of the present invention toprovide a drug delivery system for rescuing a subject from an opioidoverdose, or from preventing (or reducing the risk in) a subject (e.g.,a first responder or a member of law enforcement) from experiencing anopioid overdose.

It is also an object of certain embodiments of the present invention toprovide pharmaceutical compositions, drug delivery devices and methodsfor the treatment of alcohol dependence, constipation and otherconditions that may be treated with opioid antagonists.

The above objects and others may be achieved by the present inventionwhich in certain embodiments is directed to a pharmaceutical compositionfor providing opioid overdose rescue to a subject, or for preventing anopioid overdose in a subject. In certain embodiments, the pharmaceuticalcomposition comprises a therapeutically effective amount of an opioidantagonist, and a parenterally acceptable absorption enhancing amount ofan adjuvant that promotes, enhances, or quickens the systemic absorptionrate of the opioid antagonist post intramuscular or subcutaneousinjection. The adjuvant may be selected from appropriateabsorption-enhancing agents currently known or those that would bereadily appreciated by an ordinary skilled artisan (in formulation andmedical fields) for such use. In certain non-limiting embodiments, theadjuvant comprises nitric oxide inducers, niacin, niacin derivatives,niacin metabolites phosphodiesterase inhibitors, angiotensin convertingenzyme (ACE) inhibitors, angiotensin receptor blockers, calcium-channelblockers, nitrates or combinations thereof.

In certain embodiments, the opioid antagonist comprises naloxone,naltrexone, nalmefene, pharmaceutically acceptable salts thereof, orcombinations thereof.

In certain embodiments, the pharmaceutical composition of the presentinvention comprises a therapeutically effective amount of nalmefene or apharmaceutically acceptable salt thereof and an absorption-enhancingeffective amount of a pharmaceutically acceptable adjuvant (e.g.,parenterally acceptable adjuvant), wherein the composition provides atime to onset of action of the nalmefene of 5 minutes or less postintramuscular or subcutaneous injection to a subject experiencing, or atrisk of experiencing an opioid agonist overdose.

In certain embodiments, the composition provides a mean time to maximumplasma concentration of nalmefene of about 2.0 hours or less postintramuscular injection to a population of healthy subjects or about 1.0hour or less post subcutaneous injection to a population of healthysubjects.

In certain embodiments, the present invention is directed to an opioidoverdose rescue method or an opioid overdose prevention method to asubject experiencing or at risk of experiencing an opioid (e.g., anopioid agonist) overdose, comprising intramuscularly, or subcutaneouslyadministering to the subject a pharmaceutical composition as disclosedherein.

In certain embodiments, the present invention is directed to a drugdelivery system comprising a device containing a pharmaceuticalcomposition as disclosed herein. In one embodiment, such a device issuitable for delivering the pharmaceutical composition throughinjection. In certain embodiments, the composition is contained within apre-filled syringe, a vial, an injection pen, or an auto-injector.

BRIEF DESCRIPTION OF THE DRAWINGS

The above and other features of the present invention, their nature, andvarious advantages will become more apparent post consideration of thefollowing detailed description, taken in conjunction with theaccompanying drawings, in which:

FIG. 1 depicts the comparative mean plasma concentration profiles ofnalmefene alone at different doses (0.1 mg, 0.25 mg, and 1 mg) afterintramuscular administration in three canine subjects.

FIG. 2 depicts the mean plasma concentration profiles of nalmefene inthree canine subjects post intramuscular administration of variousnalmefene formulations (dose of 0.25 mg each) with selected adjuvants.

FIG. 3 depicts the T_(max) values of nalmefene in three canine subjectsafter intramuscular administration of various nalmefene formulations(dose of 0.25 mg each) formulated with and without selected adjuvants.

FIG. 4 depicts the C_(max) of nalmefene in three canine subjects afterintramuscular administration of three formulations in which nalmefene(dose of 0.25 mg each) was formulated with 5% (w/v), 10% (w/v), and 20%(w/v) MgCl₂, respectively.

FIG. 5 depicts the mean concentration as a function of time in humansubjects treated intramuscularly with parenteral nalmefene formulationswith various concentrations of MgCl₂, respectively.

DEFINITIONS

As used herein, the singular forms “a,” “an,” and “the” include pluralreferences unless the context clearly indicates otherwise. Thus, forexample, reference to “an opioid antagonist” includes a single opioidantagonist as well as a mixture of two or more different opioidantagonists; and reference to an “excipient” includes a single excipientas well as a mixture of two or more different excipients, and the like.

As used herein, the term “about” in connection with a measured quantityor time, refers to the normal variations in that measured quantity ortime, as expected by one of ordinary skill in the art in making themeasurement and exercising a level of care commensurate with theobjective of measurement. In certain embodiments, the term “about”includes the recited number±10%, such that “about 10” would include from9 to 11, or “about 1 hour” would include from 54 minutes to 66 minutes.

As used herein, the term “active agent” refers to any material that isintended to produce a therapeutic, prophylactic, or other intendedeffect, whether or not approved by a government agency for that purpose.This term with respect to a specific agent includes the pharmaceuticallyactive agent, and all pharmaceutically acceptable salts, solvates andcrystalline forms thereof, where the salts, solvates and crystallineforms are pharmaceutically active.

As used herein, the terms “therapeutically effective” and an “effectiveamount” refer to that amount of an active agent or the rate at which itis administered needed to produce a desired therapeutic result.

The term “subject” refers to a human or animal, who has demonstrated aclinical manifestation of an opioid overdose suggesting the need for arescue treatment, or who is at risk of being exposed to a toxic amountof an opioid. For example, in a first medical responder or lawenforcement context, the subject is treated prophylactically with anopioid antagonist. The term “subject” may include a person or animal(e.g., a canine) who is a patient being appropriately treated by amedical caregiver with an opioid to treat or prevent pain. The term“subject” may also include a person or animal who is inappropriatelyusing an opioid through misuse, abuse, or through inadvertent exposure.The term “subject” may also include a first responder (such as, an EMTresponding to a case of opioid overdose), or a member of lawenforcement, or a drug detecting canine, who are preparing to enter alocale where toxic amount of an opioid or opioids may be found. The term“subject” may also include any person who appears to a non-clinicallytrained bystander to be experiencing one or more behaviors (such as,unconsciousness, unresponsiveness, slowed breathing, or other behaviorssuggestive of opioid-induced stupor or central nervous systemdepression) associated with excessive opioid exposure.

The terms “treatment of” and “treating” include the administration of anactive agent(s) with the intent to lessen the severity of a condition.

The terms “prevention of” and “preventing” include the avoidance of theonset of a condition by a prophylactic administration of the activeagent.

The term “condition” or “conditions” may refer to those medicalconditions commonly recognized as the result of an opioid overdose, suchas unresponsiveness, respiratory depression, vomiting, limp body, paleor clammy skin, bluish fingernails or lips, slow, erratic or noheartbeat, or a combination thereof, which can be treated, mitigated orprevented by a timely administration to a subject of an effective amountof an opioid antagonist. In certain embodiments, the term “condition” or“conditions” may refer to alcohol dependence or constipation.

The term “manic behavior” refers to a medical condition that may becharacterized through physical and mental manifestations that may beexpressed by one or more of the following symptoms: irritability,anxiety, aggressiveness, violence to self or others, hypersensitivity,hypervigilance, impulsivity, a compulsion to over-explain, suddenincrease in energy levels, decreased need for sleep, hyperactivity,disorientation, incoherence, increase in risky behavior,inattentiveness, delusions, inflated self-esteem, grandiosity,distractibility, etc.

The term “combative behavior” refers to a subject's manifestation ofviolent, irritable, and/or aggressive symptoms that could result inphysical or mental harm to the subject and/or to his surroundings and/orto a person administering a medical treatment, such as administration ofan opioid antagonist.

The term “adjuvant” refers to an agent that is incorporated into apharmaceutical composition to enhance the absorption of an active agent,e.g., by increasing C_(max), shortening T_(max), or increasingbioavailability, or a combination thereof. An adjuvant may be inactivein all other respects or may provide an intended or unintendedpharmacological effect in addition to enhancing the absorption of anactive agent.

A “toxic amount of an opioid agonist” may be understood by one skilledin the art (e.g., a clinician, a first responder, and the like) as theamount of opioid agonist which would most likely cause a serious adverseevent (such as, respiratory failure, unresponsiveness, and slowbreathing etc.). Such toxic amount may vary from one opioid agonist toanother and from one individual subject to another.

The term “T_(1/2)” refers to the time for the plasma concentration of anactive agent to decrease by half.

Recitation of ranges of values herein is merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range, unless otherwise indicated herein, and eachseparate value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g., “such as”) provided herein, isintended merely to illuminate certain materials and methods and does notpose a limitation on scope. No language in the specification should beconstrued as indicating any non-claimed element as essential to thepractice of the disclosed materials and methods.

DETAILED DESCRIPTION

Dosage Forms and Pharmaceutical Compositions

According to various embodiments, the present invention is related to apharmaceutical composition for opioid overdose rescue or prevention. Incertain embodiments, the invention is directed to a pharmaceuticalcomposition comprising a therapeutically effective amount of an opioidantagonist and a pharmaceutically acceptable adjuvant (e.g., aparenterally acceptable adjuvant) that promotes the absorption rate ofthe opioid antagonist post intramuscular or subcutaneous injection. Theadjuvant may comprise nitric oxide inducers, niacin, niacin derivatives,niacin metabolites, phosphodiesterase inhibitors, angiotensin convertingenzyme (ACE) inhibitors, angiotensin receptor blockers, calcium channelblockers, nitrates or combinations thereof. Such a pharmaceuticalcomposition can provide for a quicker onset of action of the opioidantagonist as compared to the same pharmaceutical composition withoutthe adjuvant.

The opioid antagonist can be any opioid antagonist currently known orthose that would be readily appreciated by an ordinary skilled artisan(in formulation and medical fields) for such use that effectivelycounteracts or prevents an opioid overdose. In certain embodiments, theopioid antagonist comprises naloxone, naltrexone, nalmefene,pharmaceutically acceptable salts thereof, or combinations thereof. Incertain embodiments, the opioid antagonist is nalmefene.

In certain embodiments, the invention is directed to a pharmaceuticalcomposition comprising a therapeutically effective amount of nalmefeneor a pharmaceutically acceptable salt thereof and a parenterallyacceptable adjuvant, wherein the formulation provides a time to onset ofaction (i.e., the first detectable therapeutic effect associated withadministration of an opioid antagonist, e.g., detectable lessening orreduction of any of the symptoms associated with opioid overdose) ofless than 5 minutes post intramuscular or subcutaneous injection to asubject experiencing an opioid agonist overdose, or pretreating againstpotential opioid agonist exposure.

In certain embodiments, the pharmaceutical composition provides a timeto onset of action (i.e., counteracting at least one symptom of anopioid overdose) of about 4 minutes or less, about 3 minutes or less,about 2 minutes or less or about 1 minute or less post intramuscular orsubcutaneous injection to a subject experiencing an opioid agonistoverdose or needing pretreatment against potential opioid agonistexposure (i.e., prophylactic treatment). In certain embodiments, thepharmaceutical composition provides a time to onset of action (i.e.,counteracting, e.g., with clinical manifestation, at least one symptomof an opioid overdose) from greater than about 5 seconds, greater thanabout 10 seconds, greater than about 15 seconds, greater than about 30seconds, greater than about 45 seconds, or greater than about 1 minuteto less than about 5 minutes, about 4 minutes or less, about 3 minutesor less, or about 2 minutes or less post intramuscular or subcutaneousinjection to a subject experiencing an opioid agonist overdose orneeding pretreatment against potential opioid agonist exposure (i.e.,prophylactic treatment).

In other embodiments, the invention is directed to a pharmaceuticalcomposition comprising a therapeutically effective amount of nalmefeneor a pharmaceutically acceptable salt thereof and a parenterallyacceptable adjuvant, wherein the formulation provides a mean time tomaximum plasma concentration of nalmefene of about 2.0 hours or lesspost intramuscular injection to a population of subjects (e.g.,otherwise healthy subjects) or about 1 hour or less post subcutaneousinjection to a population of subjects (e.g., otherwise healthysubjects).

In other embodiments, the invention is directed to a pharmaceuticalcomposition comprising a therapeutically effective amount of nalmefeneor a pharmaceutically acceptable salt thereof and a parenterallyacceptable adjuvant, wherein the formulation provides a mean time tomaximum plasma concentration of nalmefene of about 2 hours or less,about 1.5 hours or less, about 1 hour or less, about 0.5 hour or less,about 20 minutes or less, about 15 minutes or less, or about 10 minutesor less, post intramuscular injection to a population of subjects (e.g.,otherwise healthy subjects). In other embodiments, the formulationprovides a mean time to maximum plasma concentration of nalmefene fromabout 0.1 hour or more, about 0.2 hour or more, about 0.3 hour or more,or about 0.4 hour or more to any of about 2.0 hours or less, about 1.5hours or less, about 1 hour or less, or about 0.5 hour or less postintramuscular injection to a population of subjects (e.g., otherwisehealthy subjects).

In other embodiments, the invention is directed to a pharmaceuticalcomposition comprising a therapeutically effective amount of nalmefeneor a pharmaceutically acceptable salt thereof and a parenterallyacceptable adjuvant, wherein the formulation provides an individual timeto maximum plasma concentration of nalmefene of about 2 hours or less,about 1.5 hours or less, about 1 hour or less, about 0.5 hour or less,about 20 minutes or less, about 15 minutes or less, or about 10 minutesor less, post intramuscular injection or post subcutaneous injection toa subject (e.g., otherwise healthy subject). In other embodiments, theformulation provides an individual time to maximum plasma concentrationof nalmefene from about 0.1 hour or more, about 0.2 hour or more, about0.3 hour or more, or about 0.4 hour or more to any of about 2.0 hours orless, about 1.5 hours or less, about 1 hour or less, or about 0.5 houror less post intramuscular injection or post subcutaneous injection to asubject (e.g., otherwise healthy subject).

In certain embodiments, the invention is directed to a pharmaceuticalcomposition comprising a therapeutically effective amount of nalmefeneor a pharmaceutically acceptable salt thereof and a parenterallyacceptable adjuvant, wherein the formulation provides a mean T_(1/2) ofabout 5 hours to about 20 hours, of about 7 hours to about 15 hours, ofabout 8 hours to about 12 hours or of about 9 hours to about 10 hourspost intramuscular injection or post subcutaneous injection to apopulation of subjects (e.g., otherwise healthy subjects).

In other embodiments, the invention is directed to a pharmaceuticalcomposition comprising a therapeutically effective amount of nalmefeneor a pharmaceutically acceptable salt thereof and a parenterallyacceptable adjuvant, wherein the formulation provides a mean time tomaximum plasma concentration of nalmefene of about 1 hour or less, about0.5 hour or less, about 20 minutes or less, about 15 minutes or less, orabout 10 minutes or less, post subcutaneous injection to a population ofsubjects (e.g., otherwise healthy subjects). In other embodiments, theformulation provides a mean time to maximum plasma concentration ofnalmefene from about 0.1 hour or more, about 0.2 hour or more, about 0.3hour or more, or about 0.4 hour or more to about 1.0 hour or about 0.5hours or less post subcutaneous injection to a population of subjects(e.g., otherwise healthy subjects).

In certain embodiments, the composition provides a mean time to maximumplasma concentration of nalmefene of about 3.0 hours or less, about 2.5hours or less, about 2.0 hours or less, about 1 hour or less, about 0.5hours or less, about 15 minutes or less, about 12 minutes or less, about10 minutes or less, or about 8 minutes or less post intramuscular orsubcutaneous injection to a population of subjects (e.g., otherwisehealthy subjects) and also provides an onset of therapeutic action ofless than 5 minutes, about 4 minutes or less, about 3 minutes or less,about 2 minutes or less or about 1 minute or less post intramuscular orsubcutaneous injection to a subject experiencing an opioid agonistoverdose or needing pretreatment due to potential opioid agonistexposure.

In other embodiments, the composition provides a mean time to maximumplasma concentration of nalmefene of about 2.0 hours or less postintramuscular injection to a population of subjects (e.g., healthysubjects, or otherwise healthy subjects) or about 1.0 hour or less postsubcutaneous injection to a population of subjects (e.g., healthysubjects, or otherwise healthy subjects) and also provides an onset oftherapeutic action of about 15 minutes or less, about 12 minutes orless, about 10 minutes or less, about 8 minutes or less, about 5 minutesor less, 4 minutes or less, about 3 minutes or less, about 2 minutes orless or about 1 minute or less post intramuscular or subcutaneousinjection to a subject experiencing an opioid agonist overdose orneeding pretreatment due to a potential opioid agonist exposure.

In certain embodiments, the invention is directed to a pharmaceuticalcomposition comprising a therapeutically effective amount of nalmefeneor a pharmaceutically acceptable salt thereof and a parenterallyacceptable adjuvant, wherein the formulation provides a mean time tomaximum plasma concentration of nalmefene (T_(max)) that is shorter thanthe mean time to maximum plasma concentration of nalmefene of acomparative formulation without the adjuvant, post intramuscular orsubcutaneous injection to a population of subjects (e.g., healthysubjects, or otherwise healthy subjects). For instance, the mean T_(max)of the present invention may be about 1.1 times shorter, about 1.2 timesshorter, about 1.3 times shorter, about 1.4 times shorter, about 1.5times shorter, about 1.6 times shorter, about 1.7 times shorter, about1.8 times shorter, about 1.9 times shorter, or about 2 times shorterthan that of a comparative formulation without the adjuvant.

In certain embodiments, the invention is directed to a pharmaceuticalcomposition comprising a therapeutically effective amount of nalmefeneor a pharmaceutically acceptable salt thereof and a parenterallyacceptable adjuvant, wherein the formulation provides a mean T_(1/2)that is longer than the mean time for the plasma concentration ofnalmefene of a comparative formulation without the adjuvant to decreaseby half, post intramuscular or subcutaneous injection to a population ofsubjects (e.g., healthy subjects, or otherwise healthy subjects). Forinstance, the T_(1/2) of the present invention may be about 1.1 timeslonger, about 1.2 times longer, about 1.3 times longer, about 1.4 timeslonger, about 1.5 times longer, about 1.6 times longer, about 1.7 timeslonger, about 1.8 times longer, about 1.9 times longer, or about 2 timeslonger than that of a comparative formulation without the adjuvant.

In certain embodiments, the invention is directed to a pharmaceuticalcomposition comprising a therapeutically effective amount of nalmefeneor a pharmaceutically acceptable salt thereof and a parenterallyacceptable adjuvant, wherein the formulation provides a mean maximumplasma concentration of nalmefene (C_(max)) of 1 ng/mL to about 50ng/mL, about 5 ng/mL to about 20 ng/mL, about 7 ng/mL to about 18 ng/mL,about 9 ng/mL to about 16 ng/mL, about 2 ng/mL to about 25 ng/mL, about4 ng/mL to about 21 ng/mL, about 10 ng/mL to about 21 ng/mL, about 5 toabout 18 ng/mL, about 4 ng/mL to about 10 ng/mL, or about 12.5 ng/mL toabout 21 ng/mL, post intramuscular or subcutaneous injection to apopulation of subjects (e.g., healthy subjects, or otherwise healthysubjects).

In certain embodiments, the invention is directed to a pharmaceuticalcomposition comprising a therapeutically effective amount of nalmefeneor a pharmaceutically acceptable salt thereof and a parenterallyacceptable adjuvant, wherein the formulation provides a mean maximumplasma concentration of nalmefene (C_(max)) that is greater than themean maximum plasma concentration of nalmefene of a comparativeformulation without the adjuvant, post intramuscular or subcutaneousinjection to a population of subjects (e.g., healthy subjects, orotherwise healthy subjects). For instance, C_(max) may be about 1.1times greater, about 1.2 times greater, about 1.3 times greater, about1.4 times greater, about 1.5 times greater, about 1.6 times greater,about 1.7 times greater, about 1.8 times greater, about 1.9 timesgreater, or about 2 times greater than that of a comparative formulationwithout the adjuvant.

In certain embodiments, the invention is directed to a pharmaceuticalcomposition comprising a therapeutically effective amount of nalmefeneor a pharmaceutically acceptable salt thereof and a parenterallyacceptable adjuvant, wherein the formulation provides an individualmaximum plasma concentration of nalmefene (C_(max)) of about 1 ng/mL toabout 50 ng/mL, about 2 ng/mL to about 25 ng/mL, about 4 ng/mL to about21 ng/mL, about 10 ng/mL to about 21 ng/mL, about 5 to about 18 ng/mL,about 4 ng/mL to about 10 ng/mL, or about 12.5 ng/mL to about 21 ng/mL,post intramuscular or subcutaneous injection to a subject (e.g., ahealthy subject, or an otherwise healthy subject).

In certain embodiments, the invention is directed to a pharmaceuticalcomposition comprising a therapeutically effective amount of nalmefeneor a pharmaceutically acceptable salt thereof and a parenterallyacceptable adjuvant, wherein the formulation provides a mean plasmaconcentration of nalmefene five minutes (0.083 hours) afteradministration (AUC₀₋₅) of about 0.20 ng/mL·hr to about 0.50 ng/mL·hr,about 0.30 ng/mL·hr to about 0.40 ng/mL·hr, about 0.32 ng/mL·hr to about0.35 ng/mL·hr, about 0.03 ng/mL·hr to about 1.2 ng/mL·hr, about 0.07ng/mL·hr to about 1.1 ng/mL·hr, about 0.12 ng/mL·hr to about 1 ng/mL·hr,about 0.5 ng/mL·hr to about 1 ng/mL·hr, greater than about 0.03ng/mL·hr, greater than about 0.07 ng/mL·hr, greater than about 0.12ng/mL·hr, or greater than about 0.5 ng/mL·hr, post intramuscularinjection or subcutaneous injection to a population of subjects (e.g.,healthy subjects, or otherwise healthy subjects).

In certain embodiments, the invention is directed to a pharmaceuticalcomposition comprising a therapeutically effective amount of nalmefeneor a pharmaceutically acceptable salt thereof and a parenterallyacceptable adjuvant, wherein the formulation provides a mean plasmaconcentration of nalmefene ten minutes (0.167 hours) afteradministration (AUC₀₋₁₀) in about 1.00 ng/mL·hr to about 2.00 ng/mL·hr,about 1.20 ng/mL·hr to about 1.80 ng/mL·hr, about 1.40 ng/mL·hr to about1.60 ng/mL·hr, about 0.2 ng/mL·hr to about 3 ng/mL·hr, about 0.3ng/mL·hr to about 2.8 ng/mL·hr, about 0.7 ng/mL·hr to about 2.5ng/mL·hr, about 1.3 ng/mL·hr to about 2.5 ng/mL·hr, greater than about0.2 ng/mL·hr, greater than about 0.3 ng/mL·hr, greater than about 0.7ng/mL·hr, or greater than about 1.3 ng/mL·hr, post intramuscularinjection or subcutaneous injection to a population of subjects (e.g.,healthy subjects, or otherwise healthy subjects).

In certain embodiments, the invention is directed to a pharmaceuticalcomposition comprising a therapeutically effective amount of nalmefeneor a pharmaceutically acceptable salt thereof and a parenterallyacceptable adjuvant, wherein the formulation provides a mean plasmaconcentration of nalmefene fifteen minutes (0.25 hours) afteradministration (AUC₀₋₁₅) of about 1.6 ng/mL·hr to about 3.5 ng/mL·hr,about 2.0 ng/mL·hr to about 3.0 ng/mL·hr, about 2.4 ng/mL·hr to about2.8 ng/mL·hr, about 0.5 ng/mL·hr to about 4.2 ng/mL·hr, about 0.8ng/mL·hr to about 4 ng/mL·hr, about 1.5 ng/mL·hr to about 3.8 ng/mL·hr,greater than about 0.5 ng/mL·hr, greater than about 0.8 ng/mL·hr, orgreater than about 1.5 ng/mL·hr, post intramuscular injection orsubcutaneous injection to a population of subjects (e.g., healthysubjects, or otherwise healthy subjects).

In certain embodiments, the invention is directed to a pharmaceuticalcomposition comprising a therapeutically effective amount of nalmefeneor a pharmaceutically acceptable salt thereof and a parenterallyacceptable adjuvant, wherein the formulation provides a mean plasmaconcentration of nalmefene twenty minutes (0.333 hours) afteradministration (AUC₀₋₂₀) of about 2.1 ng/mL·hr to about 5.0 ng/mL·hr,about 2.8 ng/mL·hr to about 4.0 ng/mL·hr, or about 3.3 ng/mL·hr to about3.7 ng/mL·hr, about 0.5 ng/mL·hr to about 5.8 ng/mL·hr, about 1.2ng/mL·hr to about 5.3 ng/mL·hr, about 2 ng/mL·hr to about 5 ng/mL·hr,greater than about 0.5 ng/mL·hr, greater than about 1.2 ng/mL·hr, orgreater than about 2 ng/mL·hr, post intramuscular injection orsubcutaneous injection to a population of subjects (e.g., healthysubjects, or otherwise healthy subjects).

In certain embodiments, the invention is directed to a pharmaceuticalcomposition comprising a therapeutically effective amount of nalmefeneor a pharmaceutically acceptable salt thereof and a parenterallyacceptable adjuvant, wherein the formulation provides an individualplasma concentration of nalmefene five minutes (0.083 hours) afteradministration of about 0.03 ng/mL·hr to about 1.2 ng/mL·hr, about 0.07ng/mL·hr to about 1.1 ng/mL·hr, about 0.12 ng/mL·hr to about 1 ng/mL·hr,or about 0.5 ng/mL·hr to about 1 ng/mL·hr, post intramuscular injectionor subcutaneous injection to a subject (e.g., a healthy subject, or anotherwise a healthy subject). In certain embodiments, the formulationprovides an individual plasma concentration of nalmefene at greater thanabout 0.03 ng/mL·hr, greater than about 0.07 ng/mL·hr, greater thanabout 0.12 ng/mL·hr, or greater than about 0.5 ng/mL·hr, at about fiveminutes (0.083 hours) post administration via intramuscular injection orsubcutaneous injection to a subject (e.g., a healthy subject, or anotherwise a healthy subject).

In certain embodiments, the invention is directed to a pharmaceuticalcomposition comprising a therapeutically effective amount of nalmefeneor a pharmaceutically acceptable salt thereof and a parenterallyacceptable adjuvant, wherein the formulation provides an individualplasma concentration of nalmefene at about 0.2 ng/mL·hr to about 3ng/mL·hr, about 0.3 ng/mL·hr to about 2.8 ng/mL·hr, about 0.7 ng/mL·hrto about 2.5 ng/mL·hr, or about 1.3 ng/mL·hr to about 2.5 ng/mL·hr, atabout ten minutes (0.167 hours) after administration via anintramuscular injection or subcutaneous injection to a subject (e.g., ahealthy subject, or an otherwise a healthy subject). In certainembodiments, the formulation provides an individual plasma concentrationof nalmefene at greater than about 0.2 ng/mL·hr, greater than about 0.3ng/mL·hr, greater than about 0.7 ng/mL·hr, or greater than about 1.3ng/mL·hr, at about ten minutes (0.167 hours) after administration via anintramuscular injection or subcutaneous injection to a subject (e.g., ahealthy subject, or an otherwise a healthy subject).

In certain embodiments, the invention is directed to a pharmaceuticalcomposition comprising a therapeutically effective amount of nalmefeneor a pharmaceutically acceptable salt thereof and a parenterallyacceptable adjuvant, wherein the formulation provides an individualplasma concentration of nalmefene at about 0.5 ng/mL·hr to about 4.2ng/mL·hr, about 0.8 ng/mL·hr to about 4 ng/mL·hr, or about 1.5 ng/mL·hrto about 3.8 ng/mL·hr, at fifteen minutes (0.25 hours) afteradministration via an intramuscular injection or subcutaneous injectionto a subject (e.g., a healthy subject, or an otherwise healthy subject).In certain embodiments, the formulation provides an individual plasmaconcentration of nalmefene at greater than about 0.5 ng/mL·hr, greaterthan about 0.8 ng/mL·hr, or greater than about 1.5 ng/mL·hr, at fifteenminutes (0.25 hours) after administration via an intramuscular injectionor subcutaneous injection to a subject (e.g., a healthy subject, or anotherwise a healthy subject).

In certain embodiments, the invention is directed to a pharmaceuticalcomposition comprising a therapeutically effective amount of nalmefeneor a pharmaceutically acceptable salt thereof and a parenterallyacceptable adjuvant, wherein the formulation provides an individualplasma concentration of nalmefene at about 0.5 ng/mL·hr to about 5.8ng/mL·hr, about 1.2 ng/mL·hr to about 5.3 ng/mL·hr, or about 2 ng/mL·hrto about 5 ng/mL·hr, at twenty minutes (0.333 hours) afteradministration via an intramuscular injection or subcutaneous injectionto a subject (e.g., a healthy subject, or an otherwise a healthysubject). In certain embodiments, the formulation provides an individualplasma concentration of nalmefene at greater than about 0.5 ng/mL·hr,greater than about 1.2 ng/mL·hr, or greater than about 2 ng/mL·hr,twenty minutes (0.333 hours) after administration via an intramuscularinjection or subcutaneous injection to a subject (e.g., a healthysubject, or an otherwise a healthy subject).

In certain embodiments, pharmacokinetic values described herein areobtained from a subject or a population of subjects having any of thepharmaceutical compositions disclosed herein administeredintramuscularly to their deltoid. In other embodiments, pharmacokineticvalues described herein are obtained from a subject or a population ofsubjects having any of the pharmaceutical compositions disclosed hereinadministered intramuscularly to their thigh.

In certain embodiments, the pharmacokinetic values described herein maybe obtained from an individual subject (healthy or in therapeutic needthereof) or from a plurality of subjects (healthy or in therapeutic needthereof) post a parenteral administration of any of the pharmaceuticalcompositions disclosed herein.

The role of the adjuvant is to promote or quicken the systemicabsorption rate of the opioid antagonist (e.g., nalmefene or apharmaceutically acceptable salt thereof) post intramuscular orsubcutaneous injection. In certain embodiments, the adjuvant is avasodilator. The vasodilator may be an angiotensin converting enzyme(ACE) inhibitor, an angiotensin receptor blocker, a calcium channelblocker, a nitrate or magnesium chloride.

In some embodiments, the adjuvant is magnesium chloride and is presentin the pharmaceutical composition, e.g., at a concentration ranging fromabout 0.1% (w/v) to about 50% (w/v), from about 0.1% (w/v) to about 30%(w/v), from about 5% (w/v) to about 30% (w/v), from about 1% (w/v) toabout 25% (w/v), from about 15% (w/v) to about 25% (w/v), from about0.5% (w/v) to about 5% (w/v), from about 0.5% (w/v) to about 1% (w/v),from about 0.5% (w/v) to about 1.5% (w/v), from about 0.5% (w/v) toabout 3.5% (w/v), from about 0.5% (w/v) to about 3.0% (w/v), from about2.5% (w/v) to about 3% (w/v), from about 2.0% (w/v) to about 4% (w/v),from about 2.0% (w/v) to about 3.0% (w/v), from about 4.5% (w/v) toabout 5% (w/v), about 0.9% (w/v), about 1% (w/v), about 2.8% (w/v),about 3% (w/v), about 4.7% (w/v), about 5% (w/v), about 10% (w/v), about15% (w/v), or about 20% (w/v) of magnesium chloride in thepharmaceutical composition.

In certain embodiments, the adjuvant may comprise a vasodilator that isan ACE inhibitor, e.g., enalapril, captopril, lisinopril, benazepril,enalaprilat, espirapril, fosinopril, moexipril, quinapril, ramipril,perindopril, trandolapril, pharmaceutically acceptable salts thereof orcombinations thereof. In certain embodiments, the adjuvant may comprisea vasodilator that is an angiotensin receptor blocker, e.g., valsartan,losartan, irbesartan, telmisartan, eprosartan, candesartan, olmesartan,saprisartan, tasosartan, elisartan, pharmaceutically acceptable saltsthereof or combinations thereof. In certain embodiments, the adjuvantmay comprise a vasodilator that is a calcium channel blocker, e.g.,amlodipine, anipamil, barnidipine, benidipine, bepridil, darodipine,diltiazem, efonidipine, felodipine, isradipine, lacidipine,lercanidipine, lidoflazine, manidipine, mepirodipine, nicardipine,nifedipine, niludipine, nilvadipine, nimodipine, nisoldipine,nitrendipine, perhexiline, tiapamil, verapamil, pharmaceuticallyacceptable salts thereof or combinations thereof.

In certain embodiments, the adjuvant comprises a nitric oxide inducer.The nitric oxide inducer can be, e.g., an amino acid (e.g., arginine).The nitric oxide inducer can be, without limitation, L-arginine,L-homoarginine, N-hydroxy-L-arginine, nitrosated analogs thereof,nitrosylated analogs thereof, precursors thereof or combinationsthereof. The nitrosated analogs may be, e.g., nitrosated L-arginine,nitrosated N-hydroxy-L-arginine, nitrosated L-homoarginine orcombinations thereof. The nitrosylated analogs may be, e.g.,nitrosylated L-arginine, nitrosylated N-hydroxy-L-arginine, nitrosylatedL-homoarginine or combinations thereof. Also, the precursor may be,e.g., citrulline, ornithine, glutamine, lysine or combinations thereof.In one embodiment, the adjuvant is L-arginine and is present in thepharmaceutical composition, e.g., at a concentration ranging from about0.1% to about 50%, from about 5% to about 30%, from about 15% to about25%, or about 20% (w/v) of L-arginine per pharmaceutical composition.

In certain embodiments, the nitric oxide inducer comprises arginaseinhibitors, substrates for nitric oxide synthase, nitroglycerin, amylnitrate, or combinations thereof. In certain embodiments, the arginaseinhibitor comprises, e.g., N-hydroxy-L-arginine,2(S)-amino-6-boronohexanoic or combinations thereof. In otherembodiments, the substrate for nitric oxide synthase comprisescytokines, adenosine, bradykinin, calreticulin, bisacodyl,phenolphthalein, or combinations thereof.

In other embodiments, the adjuvant comprises niacin, a niacinderivative, a niacin metabolite, or a combination thereof. The niacinderivative may be acifran, acipimox, niceritrol, isonicotinic acid,isonicotinohydrazide, pyridine carboxylic acid derivatives, 3-pyridineacetic acid, 5-methylnicotinic acid, pyridazine-4-carboxylic acid,pyrazine-2-carboxylic acid, or combinations thereof. In certainembodiments, the niacin derivative is an ester of nicotinic acid, e.g.,an alkyl ester of nicotinic acid such as methyl nicotinate. In otherembodiments, the niacin metabolite comprises nicotinuric acid,nicotinamide, 6-hydroxy nicotinamide, N-methylnicotinamide,nicotinamide-N-oxide, N-methyl-2-pyridone-5-carboxamide,N-methyl-4-pyridone-5-carboxamide, or combinations thereof. In certainembodiments, the adjuvant is niacin and is present in the pharmaceuticalcomposition at a concentration ranging from about 0.1% to about 15%,from about 0.5% to about 5%, about 1%, about 2%, or about 3% (w/v) ofniacin per pharmaceutical composition.

In certain embodiments, the adjuvant comprises a phosphodiesteraseinhibitor. The phosphodiesterase inhibitor comprises phosphodiesterase 1inhibitors, phosphodiesterase 2 inhibitors, phosphodiesterase 3inhibitors, phosphodiesterase 4 inhibitors, phosphodiesterase 5inhibitors, or combinations thereof. In other embodiments, thephosphodiesterase inhibitor comprises vinpocetine, EHNA(erythro-9-(2-hydroxy-3-nonyl)adenine), anagrelide, enoximine,cilomilast, etazolate, glaucine, ibudilast, mesembrine, rolipram,pentoxifylline, piclamilast, dipyridamole, acetildenafil, avanafil,sildenafil, tadalafil, udenafil, vardenafil, milrinone, amrinone orcombinations thereof.

In certain embodiments, the pharmaceutical composition and dosage formsdisclosed herein comprise from about 0.1%, about 0.2%, about 0.3%, about0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, orabout 1% to about 2%, about 3%, about 4%, about 5%, about 6%, about 7%,about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%,about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about60%, about 70%, or about 80% (w/v) of an adjuvant per dosage form. Incertain embodiments, the pharmaceutical composition and dosage formsdisclosed herein comprises from about 0.1% to about 30%, from about 0.5%to about 25%, or from about 1% to about 20% (w/v) of an adjuvant perdosage form.

In certain embodiments, the pharmaceutical composition may furthercomprise a therapeutically effective amount of an antipsychotic agent tocounteract manic behavior that may be triggered by the administration ofthe opioid antagonist and the sudden awakening of the subject fromoverdose to unfamiliar surroundings, possibly restrained in handcuffs orto a hospital bed, and possibly in the presence of rescue or lawenforcement personnel (such as first responders including ambulanceoperators, nurses, doctors, police officers, firefighters, GoodSamaritans, etc.). Post intramuscular or subcutaneous administration ofthe pharmaceutical composition, a therapeutically effective amount ofthe antipsychotic agent is preferably bioavailable post opioid rescue orwithin a short time (e.g., about 12 minutes or less, about 10 minutes orless, about 8 minutes or less, about 5 minutes or less, about 3 minutesor less, or about 1 minute or less) after opioid overdose rescue. Inthis manner, when a subject awakens, e.g., after being rescued, theantipsychotic agent may inhibit or reduce any combative behavior thatthe subject would otherwise manifest post awakening. In someembodiments, the manic behavior comprises a physically combativebehavior by the subject.

Active Agents

The delivery systems and pharmaceutical compositions disclosed hereininclude various active agents or their pharmaceutically acceptablesalts. Pharmaceutically acceptable salts include, but are not limitedto, inorganic acid salts such as hydrochloride, hydrobromide, sulfate,phosphate and the like; organic acid salts such as formate, acetate,trifluoroacetate, maleate, tartrate and the like; sulfonates such asmethanesulfonate, benzenesulfonate, p-toluenesulfonate, and the like;amino acid salts such as arginate, asparginate, glutamate and the like,and metal salts such as sodium salt, potassium salt, cesium salt and thelike; alkaline earth metals such as calcium salt, magnesium salt and thelike; organic amine salts such as triethylamine salt, pyridine salt,picoline salt, ethanolamine salt, triethanolamine salt,dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt and the like.

The delivery systems and pharmaceutical compositions disclosed hereininclude an opioid antagonist. The opioid antagonist may comprisenaloxone, naltrexone, nalmefene, cyclazocine, levallorphan, samidorphan,methylsamidorphan, nalodeine, alvimopan, methylnaltrexone, naloxegol,naloxol, 6β-naltrexol, axelopran, bevenopran, naldemedine, cyprodime,naltrindole, norbinaltorphimine, pharmaceutically acceptable saltsthereof, or combinations thereof.

In certain embodiments, the opioid antagonist comprises naloxone,naltrexone, nalmefene, pharmaceutically acceptable salts thereof andcombinations thereof. In one embodiment, the opioid antagonist comprisesnaloxone or a pharmaceutically acceptable salt thereof. In anotherembodiment, the opioid antagonist comprises naltrexone or apharmaceutically acceptable salt thereof. In a further embodiment, theopioid antagonist comprises nalmefene or a pharmaceutically acceptablesalt thereof (e.g., nalmefene hydrochloride).

In certain embodiments, the opioid antagonist is nalmefene or apharmaceutically acceptable salt thereof which is present in apharmaceutical formulation at about 0.05 mg/ml to about 10 mg/ml, about0.1 mg/ml to about 5 mg/ml, about 0.3 mg/ml to about 2.5 mg/ml, about0.5 mg/ml to about 1.5 mg/ml, about 2 mg/ml to about 3 mg/ml, about 1.25mg/ml, about 1 mg/ml, about 1.5 mg/ml, about 1.75 mg/ml, or about 2.0mg/ml, or about 2.5 mg/ml, and is adapted for parenteral administration.

In certain embodiments, the pharmaceutical formulation (e.g., parenteralformulation) may provide an opioid antagonist (e.g., nalmefene or apharmaceutically acceptable salt thereof) dose ranging from any of about0.25 mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about1.5 mg, about 1.75 mg, about 2.0 mg, about 2.25 mg, or about 2.5 mg toany of about 2.75 mg, about 3.0 mg, about 3.25 mg, about 3.5 mg, about3.75 mg, about 4.0 mg, about 4.25 mg, about 4.5 mg, about 4.75 mg, orabout 5.0 mg.

According to certain embodiments, the delivery systems andpharmaceutical compositions disclosed herein further comprise ananti-psychotic agent. In some embodiments, the anti-psychotic agentcomprises butyrophenones, diphenylbutylpiperidines, phenothiazines,thioxanthenes, benzamides, tricyclics, benzisoxazoles orbenzisothiazoles, phenylpiperazines, quinolinones, blonanserin,pimavanserin, sertindole, molindone, pharmaceutically acceptable saltsthereof, or combinations thereof.

In some embodiments, the anti-psychotic agent is a butyrophenone. Thebutyrophenone may comprise benperidol, bromperidol, droperidol,haloperidol, melperone, pipamperone, timiperone, spiperone,pharmaceutically acceptable salts thereof, or combinations thereof.

In some embodiments, the anti-psychotic agent is adiphenylbutylpiperidine. The diphenylbutylpiperidine may comprisefluspirilene, penfluridol, pimozide, pharmaceutically acceptable saltsthereof, or combinations thereof.

In some embodiments, the anti-psychotic agent is a phenothiazine. Thephenothiazine may comprise acepromazine, chlorpromazine, cyamemazine,dixyrazine, fluphenazine, levomepromazine, mesoridazine, perazine,periciazine, perphenazine, pipotiazine, prochlorperazine, promazine,promethazine, prothipendyl, thioproperazine, thioridazine,trifluoperazine, triflupromazine, pharmaceutically acceptable saltsthereof, or combinations thereof.

In some embodiments, the anti-psychotic agent is a thioxanthene. Thethioxanthene may comprise chlorprothixene, clopenthixol, flupentixol,thiothixene, zuclopenthixol, pharmaceutically acceptable salts thereof,or combinations thereof.

In some embodiments, the anti-psychotic agent is a benzamide. Thebenzamide may comprise sulpiride, sultopride, veralipride, amisulpride,nemonapride, remoxipride, levosulpiride, tiapride, pharmaceuticallyacceptable salts thereof, or combinations thereof.

In some embodiments, the anti-psychotic agent may comprise a tricycliccompound. The tricyclic compound may comprise carpipramine,clocapramine, clorotepine, clotiapine, loxapine, mosapramine, asenapine,clozapine, olanzapine, quetiapine, zotepine, pharmaceutically acceptablesalts thereof, or combinations thereof.

In some embodiments, the anti-psychotic agent is a benzisoxazole orbenzisothiazole. The benzisoxazole or benzisothiazole may compriseiloperidone, lurasidone, paliperidone, paliperidone palmitate,perospirone, risperidone, ziprasidone, pharmaceutically acceptable saltsthereof, or combinations thereof.

In some embodiments, the anti-psychotic agent is a phenylpiperazine or aquinolinone. The phenylpiperazine or quinolinone may comprisearipiprazole, aripiprazole lauroxil, brexpiprazole, cariprazine,pharmaceutically acceptable salts thereof, or combinations thereof.

In one embodiment, the anti-psychotic agent is haloperidol or apharmaceutically acceptable salt thereof. In another embodiment, theopioid antagonist is naloxone or a pharmaceutically acceptable saltthereof and the anti-psychotic agent is haloperidol or apharmaceutically acceptable salt thereof. In another embodiment, theopioid antagonist is naltrexone or a pharmaceutically acceptable saltthereof and the anti-psychotic agent is haloperidol or apharmaceutically acceptable salt thereof. In a further embodiment, theopioid antagonist is nalmefene or a pharmaceutically acceptable saltthereof and the anti-psychotic agent is haloperidol or apharmaceutically acceptable salt thereof.

In certain embodiments, the anti-psychotic agent, per unit dose,comprises about 2 mg to about 40 mg, about 2 mg to about 20 mg, about 5mg to about 15 mg, about 2 mg to about 10 mg, about 10 mg to about 20mg, about 5 mg to about 10 mg, about 10 mg to about 15 mg, about 15 mgto about 20 mg, or about 7 mg to about 12 mg haloperidol or apharmaceutically acceptable salt thereof suitable for intramuscular orsubcutaneous administration.

In certain embodiments, the delivery systems and pharmaceuticalcompositions disclosed herein may further comprise an active agentcomprising tranquilizers, CNS depressants, CNS stimulants, sedativehypnotics, or mixtures thereof.

In certain embodiments, the pharmaceutical composition and dosage formsdisclosed herein may comprise from about 0.1%, about 0.2%, about 0.3%,about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%,about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, or about 7%to about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about14%, about 15%, about 16%, about 17%, about 18%, about 19%, about 20%,about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about60%, about 70%, or about 80% (w/v) of an opioid antagonist, or acombination of an opioid antagonist, adjuvant, and/or antipsychoticagent, per dosage form. In certain embodiments, the pharmaceuticalcomposition and dosage forms disclosed herein may comprise from about0.1% to about 80%, from about 0.5% to about 30%, or from about 1% toabout 10% (w/v) of an opioid antagonist, or a combination of an opioidantagonist, adjuvant, and/or antipsychotic agent, per dosage form.

Prophylactic Treatment

It is an object of certain embodiments of the present invention toprovide a method to prevent or minimize an overdose of an opioid agonistin a subject that is at risk for exposure to an opioid agonist. Forexample, law enforcement personnel, first medical responders, ordrug-sniffing canines can be pre-treated with an opioid antagonistaccording to the present invention prior to entering an environment orlocale (e.g., a crime scene or emergency situation) where they suspectthat opioids (e.g., fentanyl, carfentanyl or sufentanyl) may have beenintentionally or unintentionally released, or are otherwise present.Also, workers at environmental disaster areas involving opioids may bepretreated to avoid toxicity of opioids that may be present in theenvironment. In the embodiments directed to methods of prophylactictreatment, the administered compositions can include, but not be limitedto the pharmaceutical compositions as disclosed herein. For example, theadministration of an opioid antagonist for prophylactic treatment canutilize the presently disclosed formulations for intramuscular orsubcutaneous administration or can utilize oral, nasal, pulmonary,transdermal, rectal, intravenous, buccal or sublingual routes ofadministering opioid antagonists.

Pharmaceutically Acceptable Excipients

The pharmaceutical compositions according to the present invention maycomprise one or more pharmaceutically acceptable carriers and excipientsappropriate for intramuscular or subcutaneous administration. Examplesof possible pharmaceutically acceptable carriers and excipients aredescribed in the Handbook of Pharmaceutical Excipients, AmericanPharmaceutical Association (6^(th) Edition, 2009 Publication), which isincorporated by reference herein. Carriers and excipients suitable forintramuscular and subcutaneous formulations include, but are not limitedto, antioxidants, buffering agents, diluents, surfactants, solubilizers,stabilizers, hydrophilic polymers, additional absorption or permeabilityenhancers, preservatives, osmotic agents, isotonicity agents, pHadjusting agents, solvents, co-solvents, viscosity agents, gellingagents, suspending agents or combinations thereof.

Suitable surfactants for the formulations disclosed herein include, butare not limited to Polysorbate 80 NF, polyoxyethylene 20 sorbitanmonolaurate, polyoxyethylene (4) sorbitan monolaurate, polyoxyethylene20 sorbitan monopalmitate, polyoxyethylene 20 sorbitan monostearate,polyoxyethylene (4) sorbitan monostearate, polyoxyethylene 20 sorbitantristearate, polyoxyethylene (5) sorbitan monooleate, polyoxyethylene 20sorbitan trioleate, polyoxyethylene 20 sorbitan monoisostearate,sorbitan monooleate, sorbitan monolaurate, sorbitan monopalmitate,sorbitan monostearate, sorbitan trilaurate, sorbitan trioleate, sorbitantristearate, and the like, and combinations thereof,

Suitable isotonicity agents for the pharmaceutical compositionsdisclosed herein include, but are not limited to dextrose, lactose,sodium chloride, calcium chloride, magnesium chloride, sorbitol,sucrose, mannitol, trehalose, raffinose, various polyethylene glycol(PEG), hydroxyethyl starch, glycine, and the like, and combinationsthereof.

Suitable suspending agents for the formulations disclosed hereininclude, but are not limited to microcrystalline cellulose,carboxymethylcellulose sodium NF, polyacrylic acid, magnesium aluminumsilicate, xanthan gum, and the like, and mixtures thereof. In certainembodiments, the pharmaceutical compositions may include one or moresuspending agents in an amount of from about 0.1 wt % to about 15 wt %,or from about 0.25 wt % to about 10 wt %, or from about 1 wt % to about8 wt %, of the total weight of the pharmaceutical composition.

Method of Providing Overdose Rescue

In certain embodiments, the present disclosure is directed to a methodof providing opioid overdose rescue to a subject in need thereof. Themethod comprises administering to a subject in need thereof an opioidantagonist, optionally an adjuvant, and optionally an antipsychoticagent, such that the onset of action of the antagonist is achieved insufficient time to reverse or partially reverse the overdose. In certainembodiments, the present invention is intended to be urgentlyadministered to a subject experiencing a medical emergency precipitatedby opioid agonist overdose. In such circumstances, the pharmaceuticalcomposition will typically be administered by a medical practitioner,emergency medical technician, law enforcement member, family member,acquaintance, or bystander post observing the subject experiencing thesymptoms of opioid agonist overdose. In some embodiments, the method mayfurther comprise, before the administering step, identifying that thesubject is experiencing an opioid agonist overdose.

The opioid agonist overdose treated by the present invention can resultfrom any overdose resulting from any opioid or combination of opioidscurrently known or those that would be readily appreciated by anordinary skilled artisan (in formulation and medical fields) for suchuse, including but not limited to any of the following: alfentanil,allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide,buprenorphine, butorphanol, clonitazene, codeine, desomorphine,dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine,dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene,dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine,ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine,dihydroetorphine, fentanyl and derivatives, heroin, hydrocodone,hydromorphone, hydroxypethidine, isomethadone, ketobemidone,levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol,metazocine, methadone, metopon, morphine, myrophine, narceine,nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphene,normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum,pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine,piminodine, piritramide, propheptazine, promedol, properidine,propoxyphene, sufentanil, tilidine, tramadol, pharmaceuticallyacceptable salts thereof, and combinations thereof.

In certain embodiments, the opioid antagonist is administered to asubject in an effective amount to counteract the opioid agonistoverdose. In certain embodiments, the optional anti-psychotic agent isco-administered to a subject with an antagonist and an adjuvant in aneffective amount to prevent, reduce, or counteract a manic behavior. Themanic behavior may be a physically or mentally combative behavior seenin some subjects immediately post recovery from the overdose.

In some embodiments, the opioid antagonist, adjuvant, and the optionalanti-psychotic agent are each administered separately. In otherembodiments, the opioid antagonist, adjuvant, and the optionalanti-psychotic agent are all administered together as a combination in asingle dosage form. In one embodiment, the opioid antagonist andadjuvant may be administered together as a combination and the optionalanti-psychotic agent may be administered separately. In one embodiment,the opioid antagonist and optional anti-psychotic agent may beadministered together as a combination and the adjuvant may beadministered separately. In one embodiment, the optional anti-psychoticagent and adjuvant may be administered together as a combination and theopioid antagonist may be administered separately.

In certain embodiments, the optional anti-psychotic agent isadministered to a subject before the subject returns to consciousness.In this manner, the subject may already experience a therapeutic effectof the anti-psychotic agent post awakening or shortly thereafter, whichmay serve to prevent the subject from engaging in a physically ormentally combative behavior after rescue from the opioid agonistoverdose.

In some embodiments, the opioid antagonist, adjuvant, and the optionalanti-psychotic agent are all administered via the same route ofadministration, i.e., intramuscular or subcutaneous. In otherembodiments, the opioid antagonist, adjuvant, and the optionalanti-psychotic agent are administered via different routes ofadministration. For example, the optional anti-psychotic agent may beadministered via intravenous administration, nasal administration,sublingual or buccal administration, or by inhalation.

In one embodiment, the opioid antagonist, adjuvant, and the optionalanti-psychotic agent are both administered to a subject in need thereofvia intramuscular administration.

In another embodiment, the opioid antagonist, adjuvant, and the optionalanti-psychotic agent are administered to a subject in need thereof viasubcutaneous administration.

In some embodiments, the opioid antagonist, adjuvant, and the optionalanti-psychotic agent are administered concurrently, simultaneously, orsequentially.

The term “concurrently” as used herein means that a dose of one agent isadministered prior to the end of the dosing interval of another agent.For example, a dose of an opioid antagonist with a particular dosinginterval would be concurrently administered with an anti-psychotic agentdose when administered within the dosing interval of the opioidantagonist.

The term “simultaneously” as used herein means that a dose of one agentis administered approximately at the same time as another agent,regardless of whether the agents are administered separately via thesame or different routes of administration or in a single pharmaceuticalcomposition or dosage form. For example, a dose of an opioid antagonistmay be administered separately from, but at the same time as, a dose ofan anti-psychotic agent.

The term “sequentially” as used herein means that a dose of one agent isadministered first and thereafter a dose of another agent isadministered second. For example, a dose of an opioid antagonist may beadministered first, and thereafter a dose of an anti-psychotic agent maybe administered second. The subsequent administration of the secondagent may be inside or outside the dosing interval of the first agent.

Other Indications

The pharmaceutical compositions, drug delivery devices and methodsdisclosed herein may alternatively be used for the treatment of alcoholdependence, constipation and other conditions that may be treated withopioid antagonists.

In certain embodiments, the present invention is directed to a method oftreating alcohol dependence in a subject in need thereof. Thus, themethod may comprise administering any of the pharmaceutical compositionsdisclosed herein to a subject in need thereof for the treatment ofalcohol dependence and/or its symptoms. In some embodiments, the methodmay further comprise, before the administering step, identifying thatthe subject is experiencing a symptom of alcohol dependence.

In certain embodiments, the present invention is directed to a method oftreating constipation in a subject in need thereof. Thus, the method maycomprise administering any of the pharmaceutical compositions disclosedherein to a subject in need thereof for the treatment of constipationand/or its symptoms. In some embodiments, the method may furthercomprise, before the administering step, identifying that the subject isexperiencing a symptom of constipation.

The amount of active agent in the pharmaceutical composition may beeffective to treat, counteract, or reduce the severity of the targetindication, e.g., opioid overdose, alcohol dependence, constipation,and/or one or more of their symptoms.

Drug Delivery Systems and Kits

In certain embodiments, the present invention is directed to a drugdelivery system or to a kit containing an injection device and any ofthe pharmaceutical formulations (e.g., parenteral) disclosed herein. Incertain embodiments, the injection device is pre-filled with thepharmaceutical formulation. In certain embodiments, the injection devicecomprises a syringe, a vial, an injection pen, or an autoinjector, whichis pre-filled with the pharmaceutical formulation disclosed herein.

In certain embodiments, the drug delivery system or kit may comprise anactive agent and an adjuvant in separate containers (e.g., separatevials, separate syringe barrels, separate compartments, and the like).In one embodiment, nalmefene or a pharmaceutically acceptable saltthereof may be in one container and an adjuvant (e.g., MgCl₂) may be inanother container such that the nalmefene or pharmaceutically acceptablesalt thereof may be mixed prior to administration.

In certain embodiments, the active agent (e.g., nalmefene orpharmaceutically acceptable salt thereof) in the drug delivery system orkit may be in solution or in powder form. In certain embodiments, theadjuvant in the drug delivery system or kit may be in solution or inpowder form.

In one embodiment, the drug delivery system or kit may comprise anactive agent (e.g., nalmefene or pharmaceutically acceptable saltthereof) solution in one container and an adjuvant (e.g., MgCl₂)solution in another container. The active agent solution and adjuvantsolution may be mixed prior to administration. In one embodiment, theactive agent solution may be in one compartment of an auto-injector andthe adjuvant solution may be in another compartment in an auto-injectorand the two solutions may be mixed in the auto-injector prior toadministration. In another embodiment, the active agent solution may bein one vial, the adjuvant solution may be in another vial, and thecontents of the vials may be mixed prior to administration (e.g, bytransferring the content of one vial into another vial with a syringeand needle which could be part of the kit described herein).

In one embodiment, the drug delivery system or kit described herein maycomprise an active agent (e.g., nalmefene or pharmaceutically acceptablesalt thereof) solution in one container and an adjuvant (e.g., MgCl₂)powder in another container. The active agent solution and adjuvantpowder may be mixed prior to administration. In one embodiment, theactive agent solution may be in one compartment of an auto-injector andthe adjuvant powder may be in another compartment in an auto-injectorand the powder and solution may be mixed in the auto-injector prior toadministration. In another embodiment, the active agent solution may bein one vial (or pre-filled syringe barrel or the like), the adjuvantpowder may be in another vial, and the active agent solution may beadded to the adjuvant powder (e.g., by transferring the active agentsolution into the adjuvant powder container with a syringe and needlewhich could be part of the kit described herein) to suspend or dissolvethe adjuvant powder prior to administration.

In one embodiment, the drug delivery system or kit described herein maycomprise an active agent (e.g., nalmefene or pharmaceutically acceptablesalt thereof) powder in one container and an adjuvant (e.g., MgCl₂)solution in another container. The active agent powder and adjuvantsolution may be mixed prior to administration. In one embodiment, theactive agent powder may be in one compartment of an auto-injector andthe adjuvant solution may be in another compartment of an auto-injectorand the powder and solution may be mixed in the auto-injector prior toadministration. In another embodiment, the active agent powder may be inone vial, the adjuvant solution may be in another vial (or pre-filledsyringe barrel or the like), and the adjuvant solution may be added tothe active agent powder (e.g., by transferring the adjuvant solutioninto the active agent powder container with a syringe and needle whichcould be part of the kit described herein) to suspend or dissolve theactive agent powder prior to administration.

In one embodiment, the drug delivery system or kit described herein maycomprise an active agent (e.g., nalmefene or pharmaceutically acceptablesalt thereof) powder in one container, an adjuvant (e.g., MgCl₂) powderin another container, and a solvent in yet another container. The activeagent powder, adjuvant powder, and solvent may be mixed prior toadministration. In one embodiment, the active agent powder may be in onecompartment of an auto-injector, the adjuvant powder may be in anothercompartment of an auto-injector, and a solvent may be in yet anothercompartment of an auto injection such that the powders may be suspendedor dissolved in the solvent prior to administration. In anotherembodiment, the active agent powder may be in one vial, the adjuvantpowder may be in another vial, and the solvent may be in yet anothervial (or pre-filled syringe barrel or the like), and the solvent may beadded to the active agent powder and/or to the adjuvant powder (e.g., bytransferring the solvent into the active agent powder and/or theadjuvant powder container(s) with a syringe and needle which could bepart of the kit described herein) to suspend or dissolve the powdersprior to administration.

In certain embodiments, the drug delivery system or kit described hereinmay comprise an active agent (e.g., nalmefene or pharmaceuticallyacceptable salt thereof) and an adjuvant (e.g., MgCl₂) combined togetherin a powder form in one container, and a pharmaceutically acceptablesolvent is stored in another container, prior to administration. In oneembodiment, the active agent powder and adjuvant powder may be mixedtogether in one compartment of an auto-injector and a pharmaceuticallyacceptable solvent may be stored in another compartment in an autoinjection such that the powder mixture may be suspended or dissolved inthe solvent prior to administration. In another embodiment, the activeagent powder and the adjuvant powder may be mixed together in one vial,and the solvent may be in another vial (or pre-filled syringe barrel orthe like), and the solvent may be added to the powder mixture (e.g., bytransferring the solvent into the powder mixture container with asyringe and needle which could be part of the kit described herein) tosuspend or dissolve the powder mixture prior to administration.

Concentration ranges and/or values of active agents and/or adjuvantsexpressed in % (w/v) disclosed previously refer to the finalconcentrations when all components are mixed together just prior toadministration.

EXAMPLES

The following prophetic Examples 1-3 are set forth to assist inunderstanding the invention and should not be construed as specificallylimiting the invention described and claimed herein. Such variations ofthe invention, including the substitution of any or all equivalents nowknown or later developed, which would be within the purview of thoseskilled in the art, and changes in formulation or minor changes intherapeutic design, are to be considered to fall within the scope of theinvention incorporated herein.

Example 1

TABLE 1 Component Quantity per dose (mg) Concentration (mg/ml) Nalmefeneor a 5 5 pharmaceutically acceptable salt thereof Arginine 50 50Aqueous solutions are prepared and sodium chloride is added to adjusttonicity and hydrochloric acid is added to adjust pH to about 3.8 to4.5.The solution is contained in a device suitable for intramuscular orsubcutaneous administration.

Example 2

TABLE 2 Component Quantity per dose (mg) Concentration (mg/ml) Naloxoneor a 1 2 pharmaceutically acceptable salt thereof Nicotinic acid 10 20Aqueous solutions are prepared and sodium chloride is added to adjusttonicity and hydrochloric acid is added to adjust pH to about 3.8 to4.5.The solution is contained in a device suitable for intramuscular orsubcutaneous administration.

Example 3

TABLE 3 Component Quantity per dose (mg) Concentration (mg/ml) Naloxoneor a 5 5 pharmaceutically acceptable salt thereof Magnesium Chloride 1010Aqueous solutions are prepared and hydrochloric acid is added to adjustpH to about 3.8 to 4.5. The solution is contained in a device suitablefor intramuscular or subcutaneous administration.

The following examples set forth a study performed in dogs to assist inunderstanding the invention and should not be construed as specificallylimiting the invention described and claimed herein. Such variations ofthe invention, including the substitution of any or all equivalents nowknown or later developed, which would be within the purview of thoseskilled in the art, and changes in formulation or minor changes intherapeutic design, are to be considered to fall within the scope of theinvention incorporated herein.

Example 4

Formulations of nalmefene hydrochloride alone, as well as of nalmefenehydrochloride and an adjuvant selected from L-Arginine, MgCl₂, orNicotinic Acid, were prepared in the dosages summarized in Table 4 below(calculated based on nalmefene free base). The formulations wereadministered intramuscularly to three canine subjects. Blood sampleswere drawn pre-dose and at 1 minute, 3 minutes, 6 minutes, 10 minutes,20 minutes, 1 hour, and 3 hours post-dose.

TABLE 4 Study Design Dosing Dose Group Test Article Dosing DoseConcentration Volume Number Formulation Route N= (mg) (mg/mL) (mL)Vehicle 1 Nalmefene IM 3 0.1 0.5 0.2 Saline (0.9% (w/v) NaCl) 2Nalmefene IM 3 0.25 1.25 0.2 Saline (0.9% (w/v) NaCl) 3 Nalmefene IM 31.0 5.0 0.2 Saline (0.9% (w/v) NaCl) 4 Nalmefene + IM 3 0.25 1.25 0.2 L-20% (w/v) Arginine Arginine 5 Nalmefene + IM 3 0.25 1.25 0.2 MgCl₂  5%(w/v) MgCl₂ 6 Nalmefene + IM 3 0.25 1.25 0.2 Nicotinic  1% (w/v) AcidNicotinic Acid 7 Nalmefene + IM 3 0.25 1.25 0.2 MgCl₂  5% (w/v) MgCl₂ 8Nalmefene + IM 3 0.25 1.25 0.2 MgCl₂ 10% (w/v) MgCl₂ 9 Nalmefene + IM 30.25 1.25 0.2 MgCl₂ 20% (w/v) MgCl₂

The comparative mean plasma concentration profiles of nalmefene atdifferent doses (group 1: 0.1 mg, group 2: 0.25 mg, and group 3: 1 mg)after intramuscular administration in three canine subjects are depictedin FIG. 1 .

The comparative mean plasma concentration profiles of nalmefene (dose of0.25 mg) in the presence of various adjuvants (groups 4-6) in threecanine subjects after intramuscular administration are depicted in FIG.2 . The comparative T_(max) values of nalmefene (dose of 0.25 mg) in thepresence of various adjuvants (groups 4-6) in three canine subjectsafter intramuscular administration are depicted in FIG. 3 . Theresulting mean pharmacokinetic data of the study performed on groups 4-6are summarized in Table 5 below.

The comparative C_(max) of nalmefene obtained from canine subjects thatwere administered nalmefene in the presence of 5% (w/v), 10% (w/v), and20% (w/v) MgCl₂ per pharmaceutical composition (groups 5, 8-9) aredepicted in FIG. 4 .

TABLE 5 Comparative Mean PK Parameters of Nalmefene (0.25 mg, 1.25mg/mL) in the Presence of Various Adjuvants after IM Administration inDogs Enhancers No 1% (w/v) Enhancer/ 20% (w/v) 5% (w/v) NicotinicAdjuvant Arginine MgCl₂ Acid Concentration of Nalmefene (ng/mL) Time(hours (min)) 0 hours BLOQ* BLOQ* BLOQ* BLOQ* (pre-dose) 0.0167 hours0.556 0.554 0.419 0.337 (1 minute) 0.0500 hours 0.664 2.01 1.49 1.60 (3minutes) 0.100 hours 0.940 2.63 2.68 3.11 (6 minutes) 0.167 hours 0.8383.02 3.17 4.05 (10 minutes) 0.333 hours 1.30 2.43 3.55 7.32 (20 minutes)1.00 hours 1.45 1.33 2.81 3.23 3.00 hours 0.587 0.377 0.980 1.09Parameter Animal Weight 13.1 10.8 12.4 12.2 (kg) Dose (mg/kg) 0.01940.0232 0.0203 0.0206 C_(max) (ng/mL) 1.49 3.19 3.86 7.32 T_(max) (hr)0.700 0.200 0.278 0.333 T_(1/2) (hr) 1.45 0.912 1.39 ND** MRT_(last)(hr) 1.20 0.868 1.07 0.958 AUC_(last) 3.25 3.76 6.81 9.17 (ng · hr/mL)AUC_(∞) 4.31 3.80 9.27 ND** (ng · hr/mL) Dose-normalized ValuesAUC_(last)/D 169 161 336 453 (ng · hr · kg/mL/mg) AUC_(∞) 192 164 446ND** (ng · hr · kg/mL/mg) *BLOQ means Below Level Of Quantification **NDmeans Not Detected

Example 5

The primary objectives of the clinical study were to assess thepharmacokinetics of nalmefene following parenteral administration ofvarious doses and/or formulations of nalmefene hydrochloride and toassess the early systemic exposure to nalmefene following intramuscularadministration. The secondary objective of the clinical study was toevaluate the safety and tolerability of nalmefene hydrochloridefollowing parenteral administration.

The study designed was an open-label, randomized, single dose, crossoverstudy in healthy male and female subjects to compare the pharmacokineticprofiles of nalmefene following administration of various routes, dosesand/or formulations of nalmefene hydrochloride.

Formulations of nalmefene alone, as well as of nalmefene in combinationwith various concentrations of MgCl₂, were prepared as summarized inTable 6 below. The formulations were administered intramuscularly intothe deltoid muscle using 1 mL injections to eight human subjects toevaluate the effect of MgCl₂ on the rate and extent of absorption of a1.5 mg dose of nalmefene. A ninth subject was administered only aformulation of 1.5 mg nalmefene in 1.0 mL of 0.9% MgCl₂. All nalmefenedoses in this example were calculated based on nalmefene free base.

TABLE 6 Study Design Group No. of Subjects Treated Treatment 1 8subjects Nalmefene 1.5 mg in 1.0 mL of 0% MgCl₂ 2 9 subjects Nalmefene1.5 mg in 1.0 mL of 0.9% MgCl₂ 3 8 subjects Nalmefene 1.5 mg in 1.0 mLof 2.8% MgCl₂ 4 8 subjects Nalmefene 1.5 mg in 1.0 mL of 4.7% MgCl₂

Table 7 below summarizes the pharmacokinetic data obtained from subjectstreated with the nalmefene formulations summarized in Table 6. All PKdata is expressed as nalmefene free base.

TABLE 7 Comparative PK Parameters of Nalmefene (1.5 mg/mL) in thePresence of Various Concentrations of MgCl₂ after IM Administration inHuman Subjects 0% (w/v) 0.9% (w/v) 2.8% (w/v) 4.7% (w/v) MgCl₂ MgCl₂MgCl₂ MgCl₂ Mean C_(max) (ng/mL) 9.211 16.022 10.538 7.35 Individual minC_(max) 5.31 11.7 7.04 4.76 (ng/mL) Individual max C_(max) 12.1 20 17.99.71 (ng/mL) Mean T_(max) 0.16 (9.643) 0.14 (8.889) 0.23 (14.063) 0.49(29.375) (hours(min)) Individual min T_(max) 0.13 (7.5) 0.08 (5) 0.17(10) 0.33 (20) (hours (min)) Individual max T_(max) 0.21 (12.5) 0.21(12.5) 0.33 (20) 1 (60) (hours (min)) Mean AUC_(0-2.5) 0.05 (2.75) 0.10(6.133) 0.02 (1.256) 0.01 (0.793) (ng · hr/mL (ng · min/mL)) Individualmin AUC_(0-2.5) 0.004 (0.23) 0.007 (0.4) 0.003 (0.2) 0.007 (0.43) (ng ·hr/mL (ng · min/mL)) Individual max AUC_(0-2.5) 0.13 (8.06) 0.31 (18.51)0.06 (3.8) 0.03 (1.62) (ng · hr/mL (ng · min/mL)) Mean AUC₀₋₅ 0.20(12.193) 0.45 (27.241) 0.12 (7.247) 0.07 (3.901) (ng · hr/mL (ng ·min/mL)) Individual min AUC₀₋₅ 0.08 (4.91) 0.13 (7.7) 0.05 (2.71) 0.04(2.15) (ng · hr/mL (ng · min/mL)) Individual max AUC₀₋₅ 0.44 (26.2) 0.94(56.64) 0.38 (22.6) 0.11 (6.45) (ng · hr/mL (ng · min/mL)) MeanAUC_(0-7.5) 0.48 (28.688) 1.01 (60.403) 0.35 (21.014) 0.18 (10.723) (ng· hr/mL (ng · min/mL)) Individual min AUC_(0-7.5) 0.22 (12.99) 0.38(22.81) 0.15 (8.88) 0.11 (6.34) (ng · hr/mL (ng · min/mL)) Individualmax AUC_(0-7.5) 0.82 (49.28) 1.72 (103.261) 0.95 (57.23) 0.26 (15.8) (ng· hr/mL (ng · min/mL)) Mean AUC₀₋₁₀ 0.83 (49.877) 1.61 (96.805) 0.69(41.303) 0.35 (21.19) (ng · hr/mL (ng · min/mL)) Individual min AUC₀₋₁₀0.40 (24.14) 0.75 (44.7) 0.36 (21.53) 0.22 (13.36) (ng · hr/mL (ng ·min/mL)) Individual max AUC₀₋₁₀ 1.25 (75.15) 2.49 (149.39) 1.63 (97.85)0.56 (33.8) (ng · hr/mL (ng · min/mL)) Mean AUC_(0-12.5) 1.20 (71.988)2.20 (131.758) 1.08 (64.692) 0.56 (33.837) (ng · hr/mL (ng · min/mL))Individual min AUC_(0-12.5) 0.62 (37.08) 1.20 (72.2) 0.62 (37.2) 0.38(22.61) (ng · hr/mL (ng · min/mL)) Individual max AUC_(0-12.5) 1.65(99.29) 3.18 (190.64) 2.35 (141.23) 0.91 (54.66) (ng · hr/mL (ng ·min/mL)) Mean AUC₀₋₁₅ 1.54 (92.12) 2.72 (163.334) 1.48 (88.877) 0.80(47.998) (ng · hr/mL (ng · min/mL)) Individual min AUC₀₋₁₅ 0.83 (49.95)1.62 (96.91) 0.88 (53) 0.50 (30.17) (ng · hr/mL (ng · min/mL))Individual max AUC₀₋₁₅ 2.01 (120.61) 3.80 (227.89) 3.08 (184.63) 1.29(77.28) (ng · hr/mL (ng · min/mL)) Mean AUC₀₋₂₀ 2.11 (126.448) 3.62(216.968) 2.26 (135.311) 1.32 (79.204) (ng · hr/mL (ng · min/mL))Individual min AUC₀₋₂₀ 1.23 (73.7) 2.34 (140.51) 1.32 (78.91) 0.65(38.84) (ng · hr/mL (ng · min/mL)) Individual max AUC₀₋₂₀ 2.58 (154.91)4.84 (290.394) 4.34 (260.1) 2.08 (124.92) (ng · hr/mL (ng · min/mL))Mean AUC_(0-last) 23.53 (1412.08) 26.46 (1587.318) 26.90 (1613.989)24.99 (1499.201) (ng · hr/mL (ng · min/mL)) Individual min AUC_(0-last)20.13 (1207.91) 20.63 (1237.63) 20.52 (1231) 21.54 (1292.35) (ng · hr/mL(ng · min/mL)) Individual max AUC_(0-last) 27.91 (1674.83) 32.97(1978.09) 45.73 (2744) 27.84 (1670.39) (ng · hr/mL (ng · min/mL))

The mean concentration of nalmefene in subjects treated with 1.5 mg/mLnalmefene in the presence of 0% (w/v), 0.9% (w/v), 2.8% (w/v), and 4.7%(w/v) MgCl₂ per parenteral formulation is depicted in FIG. 5 ,respectively.

In the foregoing description, numerous specific details are set forth,such as specific materials, dimensions, processes parameters, etc., toprovide a thorough understanding of the present invention. Theparticular features, structures, materials, or characteristics may becombined in any suitable manner in one or more embodiments. The words“example” or “exemplary” are used herein to mean serving as an example,instance, or illustration. Any aspect or design described herein as“example” or “exemplary” is not necessarily to be construed as preferredor advantageous over other aspects or designs. Rather, use of the words“example” or “exemplary” is simply intended to present concepts in aconcrete fashion. As used in this application, the term “or” is intendedto mean an inclusive “or” rather than an exclusive “or”. That is, unlessspecified otherwise, or clear from context, “X includes A or B” isintended to mean any of the natural inclusive permutations. That is, ifX includes A; X includes B; or X includes both A and B, then “X includesA or B” is satisfied under any of the foregoing instances. Referencethroughout this specification to “an embodiment”, “certain embodiments”,or “one embodiment” means that a particular feature, structure, orcharacteristic described in connection with the embodiment is includedin at least one embodiment. Thus, the appearances of the phrase “anembodiment”, “certain embodiments”, or “one embodiment” in variousplaces throughout this specification are not necessarily all referringto the same embodiment.

The present invention has been described with reference to specificexemplary embodiments thereof. The specification and drawings are,accordingly, to be regarded in an illustrative rather than a restrictivesense. Various modifications of the invention in addition to those shownand described herein will become apparent to those skilled in the artand are intended to fall within the scope of the appended claims.

What is claimed is:
 1. A parenteral formulation comprising an aqueoussolution comprising about 1.5 mg of nalmefene free base or an equivalentamount of a pharmaceutically acceptable salt thereof and about 0.5% toabout 1.0% (w/v) of a parenterally acceptable adjuvant, wherein theformulation provides a mean time to maximum plasma concentration ofnalmefene (T_(max)) shorter than the mean time to maximum plasmaconcentration of nalmefene of a comparative formulation without the saidadjuvant, post intramuscular or subcutaneous injection to a populationof subjects, wherein the adjuvant is magnesium chloride.
 2. Theparenteral formulation of claim 1, wherein the mean T_(max) of theformulation is about 1.1 times shorter, about 1.2 times shorter, orabout 1.3 times shorter than that of the comparative formulation withoutthe adjuvant.
 3. The parenteral formulation of claim 1, wherein theformulation comprises about 0.9% (w/v) of magnesium chloride.
 4. Theparenteral formulation of claim 1, comprising nalmefene hydrochloride inan amount equivalent to 1.5 mg nalmefene free base.
 5. The parenteralformulation of claim 1, wherein the formulation provides a mean time tomaximum plasma concentration of nalmefene (T_(max)) shorter than themean time to maximum plasma concentration of nalmefene of a comparativeformulation without the said adjuvant, post intramuscular injection to apopulation of subjects.
 6. The parenteral formulation of claim 1,wherein the formulation provides a mean time to maximum plasmaconcentration of nalmefene (T_(max)) shorter than the mean time tomaximum plasma concentration of nalmefene of a comparative formulationwithout the said adjuvant, post subcutaneous injection to a populationof subjects.
 7. A parenteral formulation comprising an aqueous solutioncomprising about 1.5 mg of nalmefene hydrochloride in an amountequivalent to 1.5 mg nalmefene free base and about 0.9% (w/v) of aparenterally acceptable adjuvant, wherein the formulation provides amean time to maximum plasma concentration of nalmefene (T_(max)) shorterthan the mean time to maximum plasma concentration of nalmefene of acomparative formulation without the said adjuvant, post intramuscularinjection to a population of subjects, wherein the adjuvant is magnesiumchloride.